Project Summary/Abstract PA-16-240 was crafted to fast-track an improved understanding of the initiation and progression of osteoarthritis (OA), with an emphasis on the contribution of aging to the process. This proposal is designed to determine the role that progressive, age-related iron accumulation in joint tissue has in the development of OA. The strategy of this work is important and logical because: (1) it is well established that iron accumulation directly contributes to increased free radical formation and reactive oxygen species; (2) the underlying pathogenesis of many inflammatory and age-associated diseases has been associated with the toxic effects of free intra- and extracellular iron ions in tissues; and (3) it has been shown that intra- and extracellular iron is responsible for pathology in joint tissues affected by non-OA conditions. The central premise of this proposal is that age-associated iron accumulation drives the pathogenesis of primary OA via oxidant damage. To best accomplish this study, a translational OA-prone guinea pig model that predictably develops naturally-occurring (spontaneous) disease with pathology similar to humans will be used. A recognized OA- resistant control strain of guinea pig will be included to represent the varying propensity for OA in people. The global hypothesis is supported by intriguing preliminary data that the OA-prone guinea pig model, but not the OA-resistant strain, has evidence for increased iron loading in their knee joints throughout OA progression. The objective of the current project is to establish that iron accumulation in joint tissue accelerates OA. Our long term goal is to identify specific therapeutic targets in the iron pathway so that appropriate interventional strategies can be investigated for prevention and/or treatment of disease. The following aims are proposed: (1) correlate the presence and severity of OA at key ages to the deposition of iron and expression of iron regulatory molecules in knee joints of OA-prone and OA-resistant guinea pigs; (2); assess the ability of systemic iron chelation to prevent the onset and/or progression of OA in OA-prone guinea pigs; and (3) demonstrate that administration of exogenous iron to the OA-resistant guinea pig strain will incite OA pathology, thereby proving a direct relationship between cellular iron accumulation and OA. The project will use a combination of structural (histology and microcomputed tomography), molecular (transcript and protein expression), and functional (gait analysis) outcomes to characterize OA and correlate it to iron accrual (systemic and local iron/ferritin quantitation). This contribution is significant because it will make major strides towards providing convincing evidence that iron is a contributor to OA, thus filling a void in the current understanding of the pathogenesis of OA. The proposed research is innovative because: (1) it has the potential to identify iron chelation therapy as an unexplored treatment for primary OA; (2) it will characterize functional movement attributed to OA that would otherwise not be elucidated by structural or molecular data; and (3) it will focus on an underutilized animal model of OA that is also valuable for studying iron metabolism. !